Zonisamide, namely 3-(sulfamylmethyl)-benzo[d]isoxazole, is a known medicament having antiepileptic, anticonvulsive and antineurotoxic activities, belonging to the class of the sulfonamides, and having the following formula:

A process for the preparation of zonisamide, disclosed in U.S. Pat. No. 4,172,896, comprises the sulfonation of 3-bromomethyl-benzo[d]isoxazole (1) with sodium sulfite to obtain benzo[d]isoxazol-3-yl-methanesulfonic acid sodium salt (2) which is then transformed into the corresponding sulfonyl chloride (3) by treatment with phosphorous oxychloride. The reaction of the latter with gas ammonia yields zonisamide (4), as reported hereinbelow.

The starting compound (1) is not commercially available. Its preparation is described in BE 624463; Chem. Pharm. Bull. 24 (1976) p. 632; and Chim. Ter. 7 (1972) p. 127 starting from 4-hydroxycoumarin (5), according to the following scheme:

Hydroxycoumarin (5) is treated with hydroxylamine to obtain benzo[d]isoxazol-3-yl-acetic acid (6) which is brominated at the alpha position to give benzo[d]isoxazol-3-yl-bromoacetic acid (7) from which 3-bromomethyl-benzo[d]isoxazole (8) is obtained by decarboxylation. The development of this process is limited in that the starting intermediate (1) is not commercially available and therefore the preparation of zonisamide is very complex. In fact, Posner reaction for the preparation of acid (6) requires the use of metal sodium. Moreover, when metal sodium is used in alcoholic solution, besides acid (6) also remarkable amounts of O-hydroxy-acetophenone-oxime as by-product are obtained. Furthermore, the decarboxylation reaction to give compound (8) requires drastic conditions, namely the presence of a large excess of 50% sulfuric acid and reflux temperature, and the resulting product is thus difficult to be isolated.
A number of alternative processes for the preparation of zonisamide are known. By way of example, JP 53077057 discloses the preparation of intermediate (9), benzo[d]isoxazol-3-yl-methanesulfonic acid, by direct sulfonation of benzo[d]isoxazol-3-yl-acetic acid (6) with sulfonic chlorohydrin/dioxane.

The use of sulfonic chlorohydrin and dioxane is disadvantageous, as these products are highly toxic and difficult to handle.
JP 54163510 describes the synthesis of zonisamide (4) starting from 2-(2-hydroxy-phenyl)-2-oxo-ethanesulfonamide (10) by formation of the corresponding 2-hydroxyimmino-2-(2-hydroxy-phenyl)ethanesulfonamide (11) and subsequent thermal cyclization.

The main drawbacks of this synthetic route are that the starting product (10) is not commercially available and the yield is low (approx. 6%, calculated on the last step). There is therefore the need for an alternative method which allows to prepare zonisamide in highly pure form and good yield, suitable for the preparation on an industrial scale.